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Tuesday, 30 December 2008

Genes That Made 1918 Flu Lethal IsolatedTuesday, 30 December 2008
By mixing and matching a contemporary flu virus with the "Spanish flu" — a virus that killed between 20 and 50 million people 90 years ago in history's most devastating outbreak of infectious disease — researchers have identified a set of three genes that helped underpin the extraordinary virulence of the 1918 virus.
Writing today (Dec. 29) in the Proceedings of the National Academy of Sciences, a team led by University of Wisconsin-Madison virologists Yoshihiro Kawaoka and Tokiko Watanabe identifies genes that gave the 1918 virus the capacity to reproduce in lung tissue, a hallmark of the pathogen that claimed more lives than all the battles of World War I combined.
"Conventional flu viruses replicate mainly in the upper respiratory tract: the mouth, nose and throat. The 1918 virus replicates in the upper respiratory tract, but also in the lungs," causing primary pneumonia among its victims, says Kawaoka, an internationally recognized expert on influenza and a professor of pathobiological sciences in the UW-Madison School of Veterinary Medicine.
"We wanted to know why the 1918 flu caused severe pneumonia."
Autopsies of 1918 flu victims often revealed fluid-filled lungs severely damaged by massive haemorrhaging. Scientists assumed that the ability of the virus to take over the lungs is associated with the pathogen's high level of virulence, but the genes that conferred that ability were unknown.
Discovery of the complex and its role in orchestrating infection in the lungs is important because it could provide a way to quickly identify the potential virulence factors in new pandemic strains of influenza, Kawaoka says. The complex could also become a target for a new class of antiviral drugs, which is urgently needed, as vaccines are unlikely to be produced fast enough at the outset of a pandemic to blunt its spread.
To find the gene or genes that enabled the virus to invade the lungs, Kawaoka and his group blended genetic elements from the 1918 flu virus with those of a currently circulating avian influenza virus and tested the variants on ferrets, an animal that mimics human flu infection.
Substituting single genes from the 1918 virus onto the template of a much more benign contemporary virus yielded, for the most part, agents that could only replicate in the upper respiratory tract. One exception, however, included a complex of three genes that, acting in concert with another key gene, allowed the virus to efficiently colonize lung cells and make RNA polymerase, a protein necessary for the virus to reproduce.
"The RNA polymerase is used to make new copies of the virus," Kawaoka explains. Without the protein, the virus is unable to make new virus particles and spread infection to nearby cells.
In the late 1990s, scientists were able to recover genes from the 1918 virus by looking in the preserved lung tissue of some of the pandemic's victims. Using the relic genes, Kawaoka's group was able to generate viruses that carry different combinations of the 1918 virus and modern seasonal influenza virus.
When tested, most of the hybrid viruses only infected the nasal passages of ferrets and did not cause pneumonia. However, one did infect the lungs, and it carried the RNA polymerase genes from the 1918 virus that allowed the virus to make the key step of synthesizing its proteins.
In 2004, Kawaoka and his team identified another key gene from the 1918 virus that enhanced the pathogen's virulence in mice. That gene makes haemagglutinin, a protein found on the surface of the virus and that confers on viral particles the ability to attach to host cells.
"Here, I think we are talking about another mechanism," Kawaoka says.
“The RNA polymerase is used to make copies of the virus once it has entered a host cell. The role of haemagglutinin is to help the virus gain access to cells.”
Reference:
Viral RNA polymerase complex promotes optimal growth of 1918 virus in the lower respiratory tract of ferrets
Tokiko Watanabe, Shinji Watanabe, Kyoko Shinya, Jin Hyun Kim, Masato Hatta, and Yoshihiro Kawaoka
PNAS, December 29, 2008, doi: 10.1073/pnas.0806959106.........
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Thursday, 25 December 2008

Recipe for capturing authentic embryonic stem cells may apply to any mammal
Thursday, 25 December 2008
Researchers have what they think may be a basic recipe for capturing and maintaining indefinitely the most fundamental of embryonic stem cells from essentially any mammal, including cows, pigs and even humans. Two new studies reported in the December 26th issue of the journal Cell, a Cell Press publication, show that a cocktail first demonstrated to work in mice earlier this year, which includes inhibitory chemicals, also can be used to successfully isolate embryonic stem cells from rats.
Authentic rat embryonic stem cells had never before been established.
The new discovery made in labs at both the University of Edinburgh and theUniversity of Southern California (USC), Los Angeles, is a major breakthrough for biomedical research, said Qi-Long Ying, an author on both studies who was at the University of Edinburgh and is now at USC. That's because it will allow researchers to readily produce genetically altered strains of rats, with conditions that mimic human disease, in a very targeted way. Austin Smith led the team at the University of Edinburgh and Ying led the USC team.
Humans and rats are physiologically more similar than humans and mice, making the study of rats more directly applicable to people, and rats' larger size also makes them easier to work with in many cases, according to the researchers. Humans and rats also tend to have similar responses to drugs.
The findings lend support to the notion that embryonic stem cells will remain in their undifferentiated, pluripotent state when they are shielded from particular outside signals. (Pluripotent refers to the ability to differentiate into any cell or tissue type). Scientists had previously thought that the maintenance of stem cells depended on activating signals from outside, including growth factors and other chemicals.
Embryonic stem cells are derived from the inner cell mass of blastocysts. Blastocysts are hollow balls of cells that form in early development. The inner cell mass is a cluster of cells inside the blastocyst that goes on to form the embryo.
Authentic embryonic stem cells are defined by three cardinal properties: unlimited symmetrical self-renewal in the lab; comprehensive contribution to primary chimeras; and generation of functional egg and sperm for genome transmission. Chimeras are produced when embryonic stem cells are inserted into a developing blastocyst and those stem cells go on to contribute to a normal embryo with cells of two origins, Ying explained. Because those embryonic stem cells can contribute to the germ line, any genetic alterations they carry – such as the loss or gain of a gene – can be passed on to the next generation.
The versatility of embryonic stem cells, combined with the ease with which they can be manipulated genetically, has provided a powerful means to elucidate gene function and create disease models via the generation of transgenic, chimeric, and knock-out animals. Although embryonic stem cells have been routinely derived from particular strains of mice since 1981, their capture from rats or other animals had remained elusive.
While human embryonic stem cell lines do exist, Ying said, it's not clear that they represent the most grounded stem cell state because the essential properties can't be demonstrated for obvious ethical reasons.
Now, Ying and Smith's teams show that a two- or three-ingredient concoction known as 2i or 3i respectively, which inhibits signals that would otherwise activate the differentiation process, maintains rat embryonic stem cells in their natural default state, allowing them to self-renew, or multiply, as generic stem cells. (The cocktails include inhibitors of GSK3, MEK, and FGF receptor tyrosine kinases.)
Most importantly, the isolated cells can produce high rates of chimerism when reintroduced into early stage embryos and can transmit through the germline, they report.
"In the past two decades, embryonic stem cells have been routinely used to create loss of function (knock-out) or gene replacement (knock-in) mutations by homologous recombination in the mouse, providing an invaluable tool for the functional characterization of genes," Ying's group wrote.
"Now, the availability of true rat embryonic stem cells provides an opportunity to adapt the technology developed in the mouse to the rat."
The new findings raise "the possibility that culture formulations based on the 3i/2i principle could facilitate derivation of embryonic stem cells from other mammals, including livestock species," Austin Smith's team wrote.
"It will also be of interest to investigate whether supernumerary human embryos cultured in 3i/2i may give rise to pluripotent cell lines that are qualitatively different from current human 'embryonic stem' cells" more like ground state rodent embryonic stem cells.
References:
Capture of Authentic Embryonic Stem Cells from Rat Blastocysts
Mia Buehr, Stephen Meek, Kate Blair, Jian Yang, Janice Ure, Jose Silva, Renee McLay, John Hall, Qi-Long Ying, Austin Smith
Cell, Volume 135, Issue 7, 1287-1298, doi:10.1016/j.cell.2008.12.007Germline Competent Embryonic Stem Cells Derived from Rat Blastocysts
Ping Li, Chang Tong, Ruty Mehrian-Shai, Li Jia, Nancy Wu, Youzhen Yan, Eric N. Schulze, Houyan Song, Chih-Lin Shieh, Martin F. Pera, Qi-Long Ying
Cell, Volume 135, Issue 7, 1299-1310, doi:10.1016/j.cell.2008.12.006First ESCs Derived from Rats ICellNEWS - Thursday, 25 December 2008
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Finding represents major breakthrough for biomedical researchThursday, 25 December 2008
Researchers at the University of Southern California (USC) have, for the first time in history, derived authentic embryonic stem (ES) cells from rats. This breakthrough finding will enable scientists to create far more effective animal models for the study of a range of human diseases.
The research will be published in the Dec. 26 issue of the journal Cell.
"This is a major development in stem cell research because we know that rats are much more closely related to humans than mice in many aspects of biology. The research direction of many labs around the world will change because of the availability of rat ES cells," says Qi-Long Ying, Ph.D., assistant professor of Cell and Neurobiology at the Keck School of Medicine of USC, researcher at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, and the study's principal investigator.
The finding brings scientists much closer to creating "knockout" rats — animals that are genetically modified to lack one or more genes — for biomedical research. By observing what happens to animals when specific genes are removed, researchers can identify the function of the gene and whether it is linked to a specific disease.
"Without ES cells it is impossible to perform precise genetic modifications for the creation of the disease model we want," he says.
"The availability of rat ES cells will greatly facilitate the creation of rat models for the study of different human diseases, such as cancer, diabetes, high blood pressure, addiction and autoimmune diseases."
Ying, a native of China, notes that this breakthrough research occurred during 2008, the Chinese year of the rat.
Embryonic stem cells are derived from a group of cells called the inner cell mass in a very early stage embryo. ES cells provide researchers with a valuable tool to address fundamental biological questions, because they enable scientists to study how genes function, and to develop animals with conditions that mimic important human diseases.
Martin Evans of Cardiff University, UK, who was last year awarded the Nobel Prize in Medicine or Physiology, established the first ES cell lines from mice in 1981. Researchers have long been working on establishing rat ES cells, but faced technical hurdles because the conventional methods developed for the derivation of mouse cells did not work in rats.
Building on recent research into how ES cells are maintained, the USC researchers found that rat ES cells can be efficiently derived and grown in the presence of the "3i medium," which consists of molecules that inhibit three specific gene signalling components (GSK3, MEK and FGF receptor kinase). This approach insulates the stem cell from signals that would normally cause it to differentiate, or turn into specialized types of body cells. By blocking these signals, Ying and colleagues found that stem cells from rats, which have previously failed to propagate at all, could be grown indefinitely in the laboratory in the primitive embryonic state.
An accompanying study led by researchers at the University of Cambridge, UK, reported similar findings, independently verifying that authentic ES cells can be established from rats. Both papers will be published in the upcoming issue of Cell.
"The development of rat embryonic stem cells, long sought by researchers around the world, is a major advance in biomedical science," says Martin Pera, Ph.D., director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC.
"These new stem cell lines will make a huge contribution to basic and applied research and drug development, by providing a technology platform for facile genetic manipulation of a mammalian species that is widely used in academic and industrial labs studying physiology, pathology and pharmacology."
Until now, authentic ES cells have never been established from humans or animals other than mice. This new key understanding into how ES cells are maintained in culture may eventually enable scientists to establish real ES cell lines from a number of other mammals, which could have significant implications for organ transplantations and the development of drug therapies, Ying says. Researchers at USC are currently working on generating the first gene knockout rat through ES cell-based technologies.
"If our work is feasible it is likely that many labs will follow up to generate different types of gene knockout rat models," he says.
"This will have a major impact on the future of biomedical research."References:
Germline Competent Embryonic Stem Cells Derived from Rat Blastocysts
Ping Li, Chang Tong, Ruty Mehrian-Shai, Li Jia, Nancy Wu, Youzhen Yan, Eric N. Schulze, Houyan Song, Chih-Lin Shieh, Martin F. Pera, Qi-Long Ying
Cell, Volume 135, Issue 7, 1299-1310, doi:10.1016/j.cell.2008.12.006Capture of Authentic Embryonic Stem Cells from Rat Blastocysts
Mia Buehr, Stephen Meek, Kate Blair, Jian Yang, Janice Ure, Jose Silva, Renee McLay, John Hall, Qi-Long Ying, Austin Smith
Cell, Volume 135, Issue 7, 1287-1298, doi:10.1016/j.cell.2008.12.007First ESCs Derived from Rats IICellNEWS - Thursday, 25 December 2008
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ZenMaster

Monday, 22 December 2008

Scientists express human gene mutations in yeast in order to study Batten disease, a fatal childhood neurodegenerative disorderMonday, 22 December 2008
Scientists report that human gene mutations expressed in yeast cells can predict the severity of Batten Disease, a fatal nervous system disorder that begins during childhood. The new study published in Disease Models & Mechanisms (DMM), describes how the extent of changes in mutated cells paralleled the severity of symptoms seen in humans.
The initial, milder symptoms of Batten disease appear in children between ages 4 and 7. Children with this disorder (also known as juvenile neuronal ceroid lipfuscinosis, or JNCL) suffer vision loss and exhibit learning difficulties and behavioural changes. This is eventually followed by the appearance of seizures, and a devastating, progressive loss of mental and physical function, eventually leading to death before young adulthood.
Mutations in the gene CLN3 cause Batten Disease, but scientists do not fully understand the role of CLN3 in cell function. Thus, in order to learn more about this gene, researchers at the University College London created a variety of mutations based on CLN3 gene defects identified in Batten disease patients. They studied the effects of these mutations in a fission yeast protein highly similar to CLN3. The research team found that human mutations that caused a severe Batten disease progression likewise caused severe cell abnormalities in the yeast. Likewise, mutations found in mild cases of Batten disease resulted in less severe yeast cell changes.
Not only does this study help researchers understand the mechanism underlying Batten disease, but this yeast model can also be used to investigate therapeutic compounds to treat Batten disease and related illnesses.

The report was written by R.L. Haines, S. Codin, and S.E. Mole at the MRC Laboratory for Molecular Cell Biology at University College London. The report is published in the January/February issue of a new research journal, Disease Models & Mechanisms (DMM), published by The Company of Biologists, a non-profit based in Cambridge, UK.
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Patient-derived Induced Stem Cells Retain Disease TraitsMonday, 22 December 2008
When neurons started dying in Clive Svendsen's lab dishes, he couldn't have been more pleased.
The dying cells – the same type lost in patients with the devastating neurological disease spinal muscular atrophy – confirmed that the University of Wisconsin-Madison stem cell biologist had recreated the hallmarks of a genetic disorder in the lab, using stem cells derived from a patient. By allowing scientists the unparalleled opportunity to watch the course of a disease unfold in a lab dish, the work marks an enormous step forward in being able to study and develop new therapies for genetic diseases.
As reported this week in the journal Nature, Svendsen and colleagues at UW-Madison and the University of Missouri-Columbia created disease-specific stem cells by genetically reprogramming skin cells from a patient with spinal muscular atrophy, or SMA. In this inherited disease, the most common genetic cause of infant mortality, a mutation leads to the death of the nerves that control skeletal muscles, causing muscle weakness, paralysis, and ultimately death, usually by age two.
The nerves that control muscles, known as motor neurons (shown here in red), are lost in the devastating genetic disease called spinal muscular atrophy, causing weakness, paralysis, and early death. A team of UW-Madison stem cell biologists recreated the hallmarks of this disease in the lab using genetically reprogrammed stem cells created from a young SMA patient’s skin. The work gives scientists the opportunity to study the full progression of a disease in the lab and should improve understanding and treatment of genetic disorders. The motor neurons shown here were grown from cells from the patient’s healthy mother. Photo: provided by Clive Svendsen.Genetic reprogramming of skin cells, first reported in late 2007 by UW-Madison stem cell biologists James Thomson and Junying Yu and a Japanese group led by Shinya Yamanaka, turns back the cells' developmental clock and returns them to an embryonic-like state from which they can become any of the body's 220 different cell types. The resulting induced pluripotent stem cells, known as iPS cells, harness the blank-slate developmental potential of embryonic stem cells without the embryo and have been heralded as a powerful potential way to study development and disease.
Just one year later, the new work is fulfilling that promise.
"When scientists study diseases in humans, they can normally only look at the tissues affected after death and then try to work out – how did that disease happen? It's a little like the police arriving at the scene of a road accident – the car's in the ditch, but they don't know how it got there or the cause of it," explains Svendsen, a professor of anatomy and neurology in the UW-Madison School of Medicine and Public Health and the Waisman Center, and co-director of the Stem Cell and Regenerative Medicine Center.
With iPS cells, he says, "Now you can replay the human disease over and over in the dish and ask what are the very early steps that began the process. It's an incredibly powerful new tool."The nerves that control muscles, known as motor neurons (shown here in red), are lost in the devastating genetic disease called spinal muscular atrophy, causing weakness, paralysis, and early death. A team of UW-Madison stem cell biologists recreated the hallmarks of this disease in the lab using genetically reprogrammed stem cells created from a young SMA patient’s skin. The work gives scientists the opportunity to study the full progression of a disease in the lab and should improve understanding and treatment of genetic disorders. The motor neurons shown here were grown from cells from the patient’s healthy mother. Photo: provided by Clive Svendsen.
In the new study, the researchers created iPS cells from stored skin cells of a young SMA patient and his mother, who does not have the disease. The cells grew well in the lab, and the group developed a new method to efficiently drive them to make large numbers of motor neurons, the cells that control muscles and that are affected in SMA.
Initially, the motor neurons thrived in both samples. But after about a month, "the accident started happening," Svendsen says, and the motor neurons from the patient-derived cells began to disappear.
"The motor neurons we got started to die in culture, just like they do in the disease. This is the first validation of a human disease that we've modelled in a culture dish," he says.
They can now begin to dissect what kills the motor neurons and why these cells alone are targeted in the disease. Past studies to understand the effects of the SMA-causing mutation have often relied on the easy-to-obtain skin cells, which are not affected in SMA and offer limited insight into how and why motor neurons die, says UW-Madison researcher Allison Ebert, lead author on the new study.
"If we start to understand more of the mechanism of why the motor neurons specifically affected in the disease are dying, then potentially new therapies can be developed to intervene at particular times early in development," she explains. Current SMA treatment options are limited, and there is no cure.
Ebert points out that the patient-derived iPS cells can offer scientific advantages over other approaches, including embryonic stem cells, for studying disease. In effect, the researchers can watch the unfolding of an accident that has already occurred, and the known clinical outcome – the course and severity of the patient's disease – should help them understand how the changes they see in the cells fit into the bigger picture of the disease.
"The development of human-derived SMA motor neurons is an important step forward for the SMA field, especially as a variety of therapeutic avenues are being examined," agrees SMA expert Christian Lorson, a professor of veterinary pathobiology at MU and an author on the paper.
"To be able to investigate therapeutic activity in these cells, whether it be novel drugs, viral vectors, oligonucleotides, or a better understanding of disease pathology, the iPS SMA motor neurons represent an excellent disease-related context."
While complex and late-hitting disorders like Alzheimer's and Parkinson's diseases will be harder to model with iPS cells, the researchers say the approach should pave the way for studies of other genetic disorders, such as Huntington's disease.
"We have to find better ways to model complex human diseases that are difficult to reproduce in animals," Svendsen says.
"iPS cells represent a promising new research tool to reach this goal."
He credits the UW-Madison Stem Cell and Regenerative Medicine Center with facilitating the work, especially by drawing on the expertise of Yu and Thomson, who pioneered the technique, to create the iPS cells used in this study.
"This is an example of how the centre is working to collaborate on campus and off campus to bring these kinds of things to fruition," he says.
Reference:
Induced pluripotent stem cells from a spinal muscular atrophy patient
Allison D. Ebert, Junying Yu, Ferrill F. Rose, Jr, Virginia B. Mattis, Christian L. Lorson, James A. Thomson & Clive N. Svendsen
Nature advance online publication 21 December 2008, doi:10.1038/nature07677.........
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Thursday, 18 December 2008

Breakthrough may offer opportunity for expanding research, drug discoveryThursday, 18 December 2008
The study, which appears in the December 18 online version of Cell Stem Cell and the January 2009 print edition of the journal, provides proof of principle that alternative sources of stem cells can be created.
The team, which included scientists from Scripps Research, Peking University, and the University of California, San Diego, conducted the studies to establish novel rat induced pluripotent stem cell lines (riPSCs) and human induced pluripotent stem cell lines (hiPSCs) by using a specific cocktail of chemicals combined with genetic reprogramming, a process whereby an adult cell is returned to its early embryonic state. Pluripotency refers to the ability of a cell to develop into each of the more than 200 cell types of the adult body.
Mimicking Human Physiology
Scientists genetically engineer embryonic stem cells to create mouse models that contain the engineered genes — so-called transgenic animals — in the hope of applying the knowledge gained from studying such mice to benefit humans. Although using mouse pluripotent embryonic stem cells has been the standard since these cells were first derived in 1981, researchers have long wanted to apply such powerful techniques to other animal species to help the study of human physiology and disease.
The major advantage of using other animal species, such as rats, is that the physiology of these animals can better mimic human physiology, for example, in studies of metabolic and neurological diseases. The size of other animals also is an advantage because larger organs and tissues are easier to work with. Because of these benefits, scientists have created transgenic animals from species other than mice, but the lack of pluripotent stem cells from these species and the tedious and imprecise techniques currently available has made the process difficult.
"Mouse models created with pluripotent embryonic stem cells are wonderful tools for understanding the fundamental biology of genes," says Sheng Ding, Ph.D., an associate professor in the Scripps Research Department of Chemistry who was senior author of the study with Peking University investigator Hongkui Deng, Ph.D.
"But in some important ways these models are less than ideal. Our demonstrated technologies will enable unprecedented and broad applications for better creating animal models from other species."
Novel and More Robust Human Pluripotent Stem Cells
In another closely related aspect of this work, Ding has also shown that a new kind of human pluripotent stem cell can now be created using the same chemical and reprogramming methods used to create the rat pluripotent stem cells. Human pluripotent stem cells hold promise for modelling human development and disease, testing drugs, and providing unlimited functional cells for cell replacement therapy.
"Recent studies have found, however, that conventional human embryonic stem cells represent a different pluripotent cell type and are not the counterpart of the conventional, and most useful, mouse embryonic stem cells," Ding says.
The issue is that pluripotent stem cells can be represented by cells from two distinct stages of embryonic development — the early pre-implantation blastocyst stage and the later post-implantation epiblast stage. Today, conventional mouse embryonic stem cells represent the pre-implantation stage pluripotent cells, and human embryonic stem cells appear to represent later post-implantation stage pluripotent cells.
Early- and late-stage cells have very different properties. For example, they respond differently to the same signals given to stem cells to differentiate into specific types of cells. The pre-implantation stage of cells will differentiate into one type of cell, while post-implantation stage of cells will turn into other types of cells. Their propensity toward specific cell types and growth properties are also different. The novel human pluripotent cells created by the scientists appear to represent the early stage of pluripotent cells — closer to well researched conventional mouse embryonic stem cells — and grow with better properties.
"The different behaviours of the pre- and post-implantation pluripotent stem cells means that findings from research done on mouse embryonic stem cells are often not translatable to work done on human embryonic stem cells," Ding says.
"With our new human pluripotent stem cells, we again have proof of principle that human stem cells can be created that are similar to mouse embryonic stem cells. The knowledge gained from mouse studies, therefore, will be more directly translatable to human cells, offering an advantage in biomedical research.".........
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Stem Cells Drug Testing Predicted to Boom under ObamaThursday, 18 December 2008
Embryonic stem cells could provide a new way of testing drugs for dangerous side effects, according to a leading British researcher.
Speaking at the British Pharmacological Society'sWinter Meeting in Brighton today (Thursday, 18 December), Christine Mummery, Professor of Developmental Biology at Leiden University Medical Centre in The Netherlands, predicts that what is currently a small and sparsely funded research area will boom in coming years.
Her views have been buoyed by the victory of US President-elect Barack Obama, who is an ardent supporter of stem cell research. The researcher also believes the UK and Europe is well placed to be at the forefront of this exciting new research area.
Professor Mummery says that it typically costs $1 billion and takes 10 years to get a new drug to market. Before any tests or trials take place on patients, millions of chemical compounds are tested on cells in the laboratory, in a bid to detect adverse effects.
For potential drugs to treat heart disease, various cell types are used for the preliminary screening - but in the second round of testing, heart cells are necessary. At the moment the only way to do this is using heart cells from animals.
But Prof Mummery believes that since researchers are able to make unlimited human heart cells from embryonic stem cells, they offer a viable and scientifically exciting alternative.
"Many drugs meant to treat other complaints also have side effects on the heart, sometimes with fatal consequences. There are recent examples of drugs being withdrawn from the market because they caused sudden cardiac death in some patients,” she said.
"Regulators now require that drugs be tested for potential effects on the heart before going to market. At present the pharmaceutical industry has no alternative but to do this using heart cells from animals.”"With the research that is now on-going in several parts of the world, including the UK, we believe using human heart cells from human embryonic stem cells can become a good and viable alternative. From a scientific point of view, it makes much more sense to use human stem cells to model human hearts."
Prof Mummery says the UK has already recognised the potential for stem-cell based drug testing by established a special public-private research programme called 'Stem Cells for Safer Medicine' or SC4SM.
"It is only a relatively small amount of money at present but it is a start. This is clearly an emerging field that will be of importance to the pharmaceutical industry, which has been reserved in embracing human embryonic stem cell technology until now because of the ethical objections from the US, where many of them have their main base,” she adds.
This is something that is expected to change very rapidly in the coming months following the election of Barack Obama.
"The UK has a head start in terms of being able to provide the technology. Working with partners across Europe, we think we can make a significant impact in terms of providing good assessment systems comparable with existing methods for predicting drug risk to the heart and discovering whether there are beneficial effects."
The potential for stem cell technology to be used in testing new drugs will be explored by both Prof Mummery and Dr Chris Denning, from the University of Nottingham, during a special symposium entitled, 'Mending a broken heart: advances and challenges of stem cell therapy,' at the British Pharmacological Society (BPS) Winter Meeting.
The symposium will also explore and discuss the challenges that lie ahead for those seeking to develop safe stem cell-based human therapies.
About the BPS
The British Pharmacological Society, including its Clinical Pharmacology Section, is the professional association for pharmacologists in the UK and is one of the leading pharmacological societies in the world.
The history of the Society dates back to 1931 when a group of pharmacologists met in Oxford and decided to form a learned society. Since those small beginnings the Society has grown to about 2,500 members, who work in academia, industry and the health services, and many are medically qualified. The Society covers the whole spectrum of pharmacology, including the laboratory, clinical and toxicological aspects.
The aims of the Society are to promote and advance pharmacology, including clinical pharmacology, by: assisting, promoting and encouraging research and providing a forum for the presentation of pharmacology; publishing the results of research; promoting and encouraging the education and training of pharmacologists; publishing material in various forms, and promoting and arranging conferences and meetings.
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ZenMaster

Wednesday, 17 December 2008

Researchers compare cranial features using 3-D modellingWednesday, 17 December 2008University of Minnesota anthropology professor Kieran McNulty (along with colleague Karen Baab of Stony Brook University in New York) has made an important contribution toward solving one of the greatest paleoanthropological mysteries in recent history – that fossilized skeletons resembling a mythical "hobbit" creature represent an entirely new species in humanity's evolutionary chain.
Discovered on the Indonesian island of Flores in 2003, controversy has surrounded the fossilized hominid skeletons of the so-called "hobbit people," or Homo floresiensis ever since. Experts are still debating whether the 18,000-year-old remains merely belong to a diminutive population of modern-day humans (with one individual exhibiting "microcephaly," an abnormally small head) or represent a previously unrecognized branch in humanity's family tree.
Using 3D modelling methods, McNulty and his fellow researchers compared the cranial features of this real-life "hobbit" to those of a simulated fossil human (of similar stature) to determine whether or not such a species was distinct from modern humans.
"[Homo floresiensis] is the most exciting discovery in probably the last 50 years," said McNulty.
"The specimens have skulls that resemble something that died a million years earlier, and other body parts reminiscent of our three-million-year-old human ancestors, yet they lived until very recently – contemporaries with modern humans."
Comparing the simulation to the original Flores skull discovered in 2003, McNulty and Baab were able to demonstrate conclusively that the original "hobbit" skull fits the expectations for a small fossil hominid species and not a modern human. Their study was published online this month in the Journal of Human Evolution.
The cranial structure of the fossilized skull, says the study, clearly places it in humanity's genus Homo, even though it would be smaller in both body and brain size than any other member. The results of the study suggest that the theorized "hobbit" species may have undergone a process of size reduction after branching off from Homo erectus (one of modern day humanity's distant ancestors) or even something more primitive.
"We have shown with this study that the process of size reduction applied to fossil hominids accounts for many features seen in the fossil skull from Flores," McNulty said.
"It becomes much more difficult, therefore, to defend the hypothesis that the preserved skull is a modern human who simply suffered from an extremely rare disorder.”
Public interest in the discovery, analysis and implications of Flores "hobbits" has been high ever since 2003, inspiring several television specials (including a recent episode of "NOVA" entitled "Alien From Earth") and other media attention.
While the debate over Homo floresiensis will continue, McNulty believes this comprehensive analysis of the relationship between size and shape in human evolution is a critical step toward eventually understanding the place of the Flores "hobbits" in human evolutionary history.
"I think the majority of researchers favour recognizing this as a new species," McNulty said about the categorization of Homo floresiensis.
"The evidence is becoming overwhelming, and this study helps confirm that view."
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ZenMaster

Some claim problems
Wednesday, 17 December 2008
Two-thirds of women who donated eggs to fertility clinics reported satisfaction with the process, but 16 percent complained of subsequent physical symptoms and 20 percent reported lasting psychological effects, according to the first study to examine the long-term effects of donation.
The research by scientists at the University of Washington included women who donated eggs at clinics in 20 states and is the largest study to explore the effects of donation in the United States, where the practice is not regulated.
"We don't know how many egg donors there are because no official records are kept and reporting is on a voluntary basis to the Centers for Disease Control and Prevention," said Nancy Kenney, UW associate professor of psychology and women studies and lead author of the study.
The researchers were surprised at the low number of women who reported an awareness of possible physical risk prior to donation. Nearly 63 percent viewed the potential physical risk as minor and 20 percent did not recall being made aware of physical risks at the time of their first donation.
"Many of these women may be forgetting that they were warned of the lesser risks, such as bloating and the discomfort from hormone injections," said Kenney.
"It has been quite a while since they read the material handed out by clinics or heard the risk lecture and it could be that they simple forgot. The age of the women also could be a factor. Risks don't mean much to young women. They may be discounting the risk. If you are 25 and are told that something may cause cancer when you are 45 that may seem to be forever."
Of those women who reported physical problems in the donation process, bloating, pain and cramping, ovarian hyper-stimulation, mood changes and irritability, and weight gain or loss were the most common complaints. Several women claimed infertility or decreased fertility or damage to their ovaries.
However, most of the women – 73 percent – reported being aware of some of psychological risks associated with egg donation prior to donating. These included the chance they might develop concern for or attachment to their eggs or to a potential or resulting offspring, concern that the donor or resulting child might want a future relationship with them, the possibility of having a genetic child in the world or the stress resulting from the donation process.
The women were split in their reasons for donating eggs. Nearly one-third (32 percent) said their motivations were completely based on helping others while almost 19 percent said financial concerns were their sole reason. The remainder cited a combination of altruistic and monetary factors for donation.
The research drew on the experiences of 80 women who donated eggs for the first time at least two years before filling out an 84-item questionnaire. Respondents donated eggs for the first time two to 15 years before completing the questionnaire and were an average of 30.6 years old when surveyed.
The study also found that:

The average payment was $3,965, with fees ranging from $1,104 to $7,313. (The most recent first donation year was 2002 and payments were converted to 2002 dollars).

Donors who said money was a very significant factor in donation received higher payments on average ($4,453) compared to those who said money was not important ($3,413).

Seventy percent of the women donated eggs more than once. Most repeat donors underwent the procedure two or three times. One woman donated eggs on nine occasions.

Forty-five percent of the women were students when they first donated.
Ninety-four percent of the students said financial compensation was a significant factor in deciding to donate compared to 57 percent of the women who were not students.

Most of the donations took place in California (23 percent), Massachusetts (7 percent), New York (7 percent), Washington (7 percent) and New Jersey (7 percent).

Kenney said a higher percentage of women who cited altruistic reasons as their primary motivation (84 percent) reported feeling happy about their donation experiences than did the women whose decisions were mainly financial (61 percent).
"We were asking these women years later and a feeling of helping may last longer than money," she said.
"We know if clinics don't offer money most women won't donate. Great Britain, where there is no paid egg donation program, for example, has a tremendous shortage of donors. But, as one of our donors said, 'if you do this just for money, you'll be sorry.'"
Kenney noted that a number of women offered suggestions to improve the donation process and complained about unequal treatment from clinics.
"Some women talked about how they were treated like delivery suppliers. Some clinics had separate entrances at the rear for donors and poorer waiting room facilities than for egg recipients. Some said they were handed a check at the end of he procedure and told 'see you around.' Others complained that they were offered limited extra health insurance for only a very limited time after a serious procedure," she said.

Monday, 15 December 2008

Single Adult Muscle Stem Cell Can Self RenewMonday, 15 December 2008
The first demonstration that a single adult stem cell can self-renew in a mammal was reported at the American Society for Cell Biology (ASCB) 48th Annual Meeting, Dec. 13-17, 2008 in San Francisco.
The transplanted adult stem cell and its differentiated descendants restored lost function to mice with hind limb muscle tissue damage.
The adult stem cells used in the study, conducted at Stanford University, were isolated from a mixed population of satellite cells in the skeletal muscle of mice.
The skeletal adult muscle stem cells (MusSC), which live just under the membrane that surrounds muscle fibres, normally respond to tissue damage by giving rise to progenitor cells that become myoblasts, fusing into myofibers to repair the tissue damage.
The scientists transplanted the MusSC into special immune-suppressed "nude" mice whose muscle satellite cells had been wiped out in a hind limb by irradiation.
The mice would only be able to repair injury if the transplanted MuSC "took." The scientists, Alessandra Sacco and Helen Blau, had genetically engineered the transplanted MusSC to express Pax7 and luciferase proteins. As a result, every transplanted cell glowed under ultraviolet light and was easy to trace.
"To be able to detect the presence of the cells by bioluminescence was really a breakthrough," says Blau.
"It taught us so much more. We could see how the cells were responding, and really monitor their dynamics."
Through luminescent imaging as well as quantitative and kinetic analyses, Sacco and Blau tracked each transplanted stem cell as it rapidly proliferated and engrafted its progeny into the irradiated muscle tissue.
The scientists then injured the regenerated tissue, setting off massive waves of muscle cell growth and repair, and subsequently showed that the MuSC and descendents rescued the second animal's lost muscle healing function.
After isolating the luciferase-glowing muscle stem cells from the transplanted animal, the scientists duplicated, or cloned, the cells in the lab. Like the original MuSC, the cloned copies were intact and capable of self-renewal.
"We are thrilled with the results," says Sacco.
"It's been known that these satellite cells are crucial for the regeneration of muscle tissue, but this is the first demonstration of self-renewal of a single cell."
The ability to isolate and then transplant skeletal adult muscle stems cells could have a wide impact in treating not only a variety of muscle wasting diseases such as muscular dystrophy but also severe muscle injuries or loss of function from aging and disuse.
In other experiments, the researchers transplanted between 10 and 500 luciferase-tagged MuSC into the leg muscles of mice.
These cells also proliferated and engrafted, forming new myofibers and fusing with injured fibres.
Unlike tumour cells, the transplanted stem cells achieved homeostasis, growing to a stable, constant level and ceasing replication.
After demonstrating that the transplanted stem cells proliferated and fully restored the animal's lost function, Sacco and Blau recovered new stem cells from the transplant with full stem cell potency, meeting the final "gold standard" test for adult multipotent stem cells.
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ZenMaster

First trials with miceMonday, 15 December 2008
Up until today scientists assumed that the adult heart is unable to regenerate. Now, researchers and cardiologists from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and the Charité – Universitätsmedizin Berlin (Germany) have been able to show that this dogma no longer holds true. Dr. Laura Zelarayán and Assistant Professor Dr. Martin W. Bergmann were able to show that the body’s own heart muscle stem cells do generate new tissue and improve the pumping function of the heart considerably in an adult organism, when they suppress the activity of a gene regulator known as beta-catenin in the nucleus of the heart cells.
The gene regulator beta-catenin plays an important role in the development of the heart in embryos. Dr. Zelarayán and Dr. Bergmann could now show that beta-catenin is also important for the regeneration of the adult heart. They suppressed this factor in the nucleus of the heart cells in mice.
This way they activated heart precursor cells (stem cells) to turn on the regeneration of heart in adult mice. Four weeks after blocking beta-catenin, the pumping function of the heart of the animals had improved and the mice survived an infarction much better than those animals with a functioning beta-catenin gene. An important contribution to this project has been a transgenic mouse line generated by Professor Walter Birchmeier`s (MDC) laboratory.
Markers identified for Heart Muscle Stem Cells
In addition, the researchers have proven that heart muscle stem cells exist. So far, these cells had not been characterized clearly. They could demonstrate that two markers for heart cells – the structural protein alpha myosin heavy chain and the transcription factor Tbx5 - are also expressed on heart precursor cells.
"The evidence of cells with these markers in the adult heart demonstrates that stem cells dating back from heart development survive in niches in the adult heart", Dr. Bergmann explains.
The researchers in Germany collaborated with scientists in the Netherlands and Belgium. For this research, Dr. Bergmann was awarded the Wilhelm P. Wintersteinpreis this summer. The research group of Dr. Bergmann, a guest researcher at the MDC who recently became Deputy of the Department of Cardiology at the Asklepios Clinic St. Georg in Hamburg, belongs to the research group of Professor Rainer Dietz (MDC and Charité).
Reference:
Beta-catenin downregulation attenuates ischemic cardiac remodeling through enhanced resident precursor cell differentiation
Laura Zelarayán, Claudia Noack, Belaid Sekkali, Jana Kmecova, Christina Gehrke, Anke Renger, Maria-Patapia Zafiriou, Roel van der Nagel, Rainer Dietz, Leon J. de Windt, Jean-Luc Balligand and Martin W. Bergmann
PNAS, online December 10, 2008, doi: 10.1073/pnas.0808393105.........
ZenMaster

Functional Stem-cell Niche Model CreatedMonday, 15 December 2008
Like it or not, your living room probably says a lot about you. Given a few uninterrupted moments to poke around, a stranger could probably get a pretty good idea of your likes and dislikes, and maybe even your future plans. Scientists at the Stanford University School of Medicine employing a similar "peeping Tom" tactic to learn more about how stem cells develop have taken a significant step forward by devising a way to recreate the cells' lair — a microenvironment called a niche — in an adult animal.
"We have isolated the cells in mouse bone that make bone and cartilage from scratch and attract wandering blood stem cells," said Irving Weissman, MD, the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research and the director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine.
"The stem cells can and do settle in these 'niches' and make blood that is exported to the body."
The research marks the first time that scientists have successfully recreated a functional stem-cell niche for further study. Weissman and his colleagues plan to use the model system to determine how the niche environment interacts with the blood stem cells to affect their development and fate, and how leukaemia’s respond to these niches. They will also investigate the bone and cartilage healing capacity of these cells.
Weissman is the senior author of the study, which will be published Dec.10 in the advance online issue of Nature. Graduate student Charles Chan shares first authorship with postdoctoral scholars Ching-Cheng Chen, PhD, and Cynthia Luppen, PhD.
Blood-forming stem cells typically reside in the bone marrow. The researchers found that a specific subset of foetal mouse bone cells could not only take up residence and produce bone when injected near the kidney of an adult animal, but they also generated a bone marrow cavity that sheltered host-derived blood stem cells. In contrast, other subsets of foetal bone cells generated only bone.
"An amazing part of this study was the formation of organized bone, cartilage and blood stem cell niches from an initially dispersed set of cells," said Weissman, who is also a member of the Stanford Cancer Center.
"If we can find the daughter cell in this population that is responsible for niche formation, we may learn enough to eventually be able to expand blood stem cell numbers so that a small number, say from umbilical cord blood, can be made into enough to treat several patients with failure of blood formation."
Suppressing the expression of factors involved in a specialized bone-building process called endochondrial ossification in the host mouse stopped the formation of the marrow cavity and the recruitment of host stem cells. Using similar foetal bone cells from parts of the skeleton that do not undergo the process — such as the skull and the jaw — also blocks cavity formation. The findings suggest that endochondrial ossification is a necessary step in setting up house for stem cells.
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ZenMaster

Fat cells treat spinal cord injury
Monday, 15 December 2008
A study published in the current issue of Cell Transplantation (Vol.17, No. 8) suggests that mature adipocytes - fat cells - could become a source for cell replacement therapy to treat central nervous system disorders.
According to the study's lead researcher, Dr. Yuki Ohta of the Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan, adipose-derived stem/stromal cells have in the past been shown to differentiate into neuronal cells in an in vitro setting. In their study, for the first time fat cells have been shown to successfully differentiate into neuronal cells in in vivo tests. The fat cells are grown under culture conditions that result in them becoming de-differentiated fat (DFAT) cells.
"These cells, called DFAT cells, are plentiful and can be easily obtained from adipose tissue without discomfort and represent autologous (same patient) tissue," said Ohta.
"DFAT cells, with none of the features of adipocytes, do have the potential to differentiate into endothelial, neuronal or glial lineages."
The research team reported that DFAT cells expressed neurotrophic factors, such as BDNF and GDNF, prior to and after transplantation and which likely contributed to the promotion of functional recovery.
According to Ohta and colleagues, tests in animal models confirmed that the injected cells survived without the aid of immunosuppression drugs and that the DFAT-grafted animals showed significantly better motor function than controls.
"We concluded that DFAT-derived neurotrophic factors contributed to promotion of functional recovery after spinal cord injury (SCI)," said Ohta.
"Transplanting DFAT cells into SCI rats significantly promoted the recovery of their hind limb function."
"These studies demonstrate the ability to obtain stem cells from a patient's own fat that can help repair injury to the spinal cord," said Paul R. Sanberg, PhD, DSc, at the University of South Florida Health, and Coeditor-in-chief of Cell Transplantation.
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ZenMaster

Sunday, 7 December 2008

The Beauty of Cell Division
Sunday, 07 December 2008
Cell division is one of the most fundamental processes of life. It explains how one cell can give rise to an organism of several million cells, it determines the shape of different life forms and it underpins our body's capacity to heal when injured. Often we only notice how important cell division really is when it goes wrong and results in cancer or other diseases. But apart from being crucial for biology, cell division is also a very beautiful process as these images taken by Joël Beadouin in the group of Jan Ellenberg at the European Molecular Biology Laboratory show.
The pictures were taken through a confocal microscope and show the different steps of cell division in a human cell magnified approximately 650 times.

Credit: Joël Beadouin, EMBL

From left to right: When not dividing, the genetic material of a cell (DNA in blue) is found loosely in the nucleus, where a second copy of it is made in preparation for division. At the onset of division, the DNA condenses into distinct chromosomes, the nucleus breaks down and protein filaments called microtubules (green) form a spindle apparatus. The spindle aligns the chromosomes in the middle of the cell and in the next step pulls a copy of each chromosome towards the opposite poles of the cell. After this division of the genetic material, or mitosis, is completed, the rest of the cell divides. A band formed by another type of protein filaments, called actin (red), squeezes the mother cell in half to create two identical daughters. The whole process takes approximately 90 minutes.
The images were taken as part of Mitocheck, an international research project funded by the European Commission that tries to identify and characterize all the genes necessary for cell division in human cells.
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ZenMasterFor more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/ and
http://www.geocities.com/giantfideli/index.html

Friday, 5 December 2008

Researchers find a novel mechanism for a healthier heart
Friday, 05 December 2008
Results from the European study IMMIDIET show that moderate wine intake is associated with higher levels of omega-3 fatty acids considered as protective against coronary heart disease
Moderate alcohol intake is associated with higher levels of omega-3 fatty acids in plasma and red blood cells. This is the major finding of the European study IMMIDIET that will be published in the January issue of the American Journal of Clinical Nutrition, an official publication of the American Society for Nutrition. The study suggests that wine does better than other alcoholic drinks. This effect could be ascribed to compounds other than alcohol itself, representing a key to understand the mechanism lying behind the heart protection observed in moderate wine drinkers.
The IMMIDIET study examined 1,604 citizens from three geographical areas: south-west London in England, Limburg in Belgium and Abruzzo in Italy. Thanks to a close cooperation with General Practitioners of these areas, all participants underwent a comprehensive medical examination, including a one year recall food frequency questionnaire to assess their dietary intake, alcohol consumption included.
Omega-3 fatty acids, mainly derived from fish, are considered as protective against coronary heart disease and sudden cardiac death, thus their high blood concentration is definitely good for our health.
Now European researchers found that moderate alcohol drinking acts like a 'trigger', boosting the amount of omega-3 fatty acids in our body.
"Several studies have shown that moderate alcohol consumption, including wine, is associated with protection against coronary heart disease and ischemic stroke,” says Romina di Giuseppe, lead author of the study, from the Research Laboratories at Catholic University of Campobasso.
“Although the mechanisms are not completely defined, there was some evidence that alcohol intake might influence the metabolism of essential polyunsaturated fatty acids, as omega-3. That is exactly what we found in our population study. People drinking moderate amounts of alcohol, one drink a day for women and two for men, had higher concentration of omega-3 fatty acids in plasma and red blood cells independently of their fish intake".
However important these results appear to be, the best is yet to come. Researchers from Catholic University of Campobasso, in Italy, and from University of Grenoble, in France, turned their attention on the variety of alcoholic beverages consumed in order to see whether the high levels of omega-3 fatty acids detected might be ascribed to alcohol itself or to other substances.
"From our previous studies we know that association between wine drinking and increased concentration of omega-3 fatty acids have been observed,” says Michel de Lorgeril, from the University of Grenoble, partner of the IMMIDIET project and co-leader of the study.
“Nevertheless, it was not possible to separate the effects of wine from those of beer or spirits. Our study of 3 populations with different dietary habits and different consumption of alcoholic beverages types allowed us to explore this aspect.""Analysis carried out on different alcoholic beverages,” argues Licia Iacoviello coordinator of the IMMIDIET study at Catholic University of Campobasso, “showed that the association between alcohol and omega-3 fatty acids was present in both wine drinkers and beer or spirits drinkers. However, the association was stronger between wine drinking and omega-3 fatty acids levels. This suggests that components of wine other than alcohol is associated with omega-3 fatty acids concentration. We may guess this effect can be ascribed to polyphenols".
Polyphenols are naturally occurring compounds contained in a different variety of food and beverages, such as wine. Due to their strong antioxidant activity, they are able to reduce oxidation processes caused by free radicals.
"We consider these data to be a major finding," de Lorgeril concludes, "opening a new window in the field of cardiovascular prevention. Beyond the alcohol issue, our results raise crucial questions regarding the effects of polyphenols on lipids (both in blood and cell membranes) and possibly of lipids on polyphenols".About The IMMIDIET study:
Funded by the European Union under Key Action 1: Food, Nutrition and Health QLK1-CT-2000-00100, IMMIDIET aims to acquire fundamental knowledge in the field of cardiovascular disease, especially regarding the interaction between genetics and lifestyle.
At the core of the study, there is an important episode of Italian migration: Belgium, a country that became the new home for thousands of Italians, mostly from the Abruzzo region, who came to work in the mines. Many of those emigrants did not come back to Italy but remained in their new country. Some of them married a Belgian partner. Their genes remained the same, of course, but how much "Italy" is still there in their diet? And how much did they transmit it to their spouses? Moreover, how many Italian emigrants assimilate dietary habits of the country in which they were guests? In this framework, the role of genetic factors and lifestyle can be assessed to explore new ways in prevention of cardiovascular diseases.
To carry on the research, married couples have been recruited in three European areas: South-East London in England, Limburg in Belgium and Abruzzo in Italy. In the first phase of the study the couples involved were formed by people from the same area, Italians married with Italians (in the Abruzzo region), Belgians married with Belgians (in the Limburg area) and English married with English (in the South-East part of London)".
The second phase of IMMIDIET recruited mixed Italian–Belgian couples to understand if, acquiring dietary habits from Abruzzo, the Belgian partner changed his own risk regarding heart diseases.
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ZenMaster

Dormant Stem Cells for EmergenciesFriday, 05 December 2008
Many specialized cells, such as in the skin, intestinal mucosa or blood, have a lifespan of only a few days. For these tissues to function, a steady replenishment of specialized cells is indispensable. This is the task of so-called "adult" stem cells also known as tissue stem cells.
Stem cells have two main characteristics: First, they are able to differentiate into all the different cell types that make up their respective tissue – a property called pluripotency. Second, they need to renew themselves in order to be able to supply new specialized tissue cells throughout life. These processes have best been studied in mouse bone marrow.
Up to now, scientists have assumed that adult stem cells have a low division rate. According to theory, they thus protect their DNA from mutations, which happen particularly during cell division and can lead to transformation into tumour stem cells. However, the actual number of divisions of a blood stem cell throughout an organism's lifespan has remained unknown.
Professor Dr. Andreas Trumpp and Dr. Anne Wilson have now discovered a group of stem cells in mouse bone marrow that remain in a kind of dormancy almost throughout life. Trumpp, who has been head of the Cell Biology Division at DKFZ since summer 2008, had carried out these studies at the Ecole Polytechnique Fédérale in Lausanne, Switzerland, jointly with colleagues at the Ludwig Institute for Cancer Research located in the same city.
The scientists labelled the genetic material of all mouse blood cells and subsequently investigated how long this label is retained. With each division, the genetic material is apportioned to the daughter cells and, thus, the labelling dilutes. During these studies, the investigators discovered the dormant stem cells which divide only about five times throughout the life of a mouse. Translated to humans, this would correspond to only one cell division in 18 years. Most of the time, these cells, which constitute no more than about 15 percent of the whole stem cell population, remain in a kind of dormancy with very low metabolism. In contrast, stem cells of the larger group, the "active" stem cells, divide continuously about once a month.
However, in an emergency such as an injury of the bone marrow or if the messenger substance G-CSF is released, the dormant cell population awakes. Once awakened, it shows the highest potential for self-renewal ever to be observed in stem cells. If transplanted into irradiated mice, these cells replace the destroyed bone marrow and restore the whole hematopoietic system. It is possible to isolate new dormant stem cells from the transplanted animals and these cells are able to replace bone marrow again – this can be done several times in a row. The situation is different with "active" stem cells, where bone marrow replacement can successfully be carried out only once.
"We believe that the sleeping stem cells play almost no role in a healthy organism," Trumpp explains.
"The body keeps its most potent stem cells as a secret reserve for emergencies and hides them in caves in the bone marrow, also called niches. If the bone marrow is damaged, they immediately start dividing daily, because new blood cells are needed quickly."
Once the original cell count is restored and the bone marrow is repaired, these stem cells go back to deep sleep. The larger population of "active" stem cells, however, keeps up the physiological balance of blood cells in the normal healthy state.
Andreas Trumpp expects that these results may give valuable impetus to our understanding of cancer stem cells.
"Cancer stem cells, too, probably remain in a dormant state most of the time – we think that this is one of the reasons why they are resistant to many kinds of chemotherapy that target rapidly growing cells. If we were able to wake up these sleepers before a patient receives treatment, it might be possible to also eliminate cancer stem cells for the first time and, thus, to treat the disease much more effectively by destroying the supply basis."
In a second article, Dr. Elisa Laurenti from Trumpp's team shows that the two cancer genes c-Myc and N-Myc play a vital role in the functioning of stem cells. The two genes provide the blueprints for what are called transcription factors, which in turn regulate the activity of other genes and are overactive particularly in cancer cells. If both c-Myc and N-Myc are switched off at the same time in mice, the animals quickly start suffering from a general lack of blood cells and quickly die.
The two genes are not only responsible for survival of nearly all blood cells, but they also jointly control the two prime characteristics of stem cells – the capability of self-renewal and the potential to produce differentiated blood cells. This result is not only relevant for our understanding of stem cells, but it also explains the damage that can be caused by overactive Myc genes.
"In tumours, too, c-Myc and N-Myc are presumably responsible for the self-renewal of cancer stem cells and, thus, for uncontrolled growth," Trumpp explains.
References:
Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.
Anne Wilson; Gabriela Oser; Richard van der Wath; William Blanco; Elisa Laurenti; Maike Jaworski; Cyrille Durant; Leonid Eshkind; Ernesto Bockamp; Pietro Lio; Robson MacDonald, and Andreas Trumpp
Cell 2008, DOI 10.1016/j.cell.2008.10.048Hematopoietic Stem Cell Function and Survival Depend on c-Myc and N-Myc Activity.
Elisa Laurenti, Barbara Varnum-Finney, Anne Wilson, Isabel Ferrero, William E. Blanco-Bose, Armin Ehninger, Paul S. Knoepfler, Pei-Feng Cheng, H. Robson MacDonald, Robert N. Eisenman, Irwin D. Bernstein, and Andreas Trumpp
CellL Stem Cell 2008, DOI 10.1016/j.stem.2008.09.005.........
ZenMaster

Largest study of fertility patients shows concerns about embryo dispositionFriday, 05 December 2008
Fertility patients who are done having children feel responsible for the stored, frozen embryos left over from their treatment, yet more than half are against implanting the embryos in anyone else, according to a new study by researchers at Duke University Medical Center.
"This really turns our moral presumptions on their heads," says Anne Drapkin Lyerly, MD, an obstetrician/gynaecologist and bioethicist at Duke, and lead investigator of the findings that appear online in Fertility & Sterility.
"Parents care very much about what happens to their embryos, but that doesn't mean they want them to become children. Our study shows that many feel they have to do what they can to prevent their embryo from becoming a child."
The survey of more than 1,000 fertility patients is the largest and only multi-site study to shed important light on the state of the nation's 500,000 frozen embryos currently in storage. It reveals previously unexplored concerns that patients have about their embryos, and it comes at a time when several states and even the federal government are attempting to enact legislation that would either assert an embryo is a person, allow abandoned embryos to be adopted by another couple, or allow unused embryos to become "wards of the state."
What to do with those unused embryos has also become a sticking point for providers, since they are held responsible for safe storage or disposition of apparently abandoned embryos.
Fresh embryos are used in more than 80% of fertility treatment cycles, but most patients also choose to freeze some embryos that were created but not implanted, to use as a possible backup. This means that extra embryos often remain after treatment is completed. Previous studies have found that when childbearing is complete, as many as 70 percent of patients put off for five years — or more — the decision of what to do with those frozen embryos, even while they continue to pay annual storage fees. In Lyerly's study, 20 percent of the patients who had completed childbearing indicated they were likely to freeze their embryos "forever."
The lack of acceptable options fuels patients' reluctance to make a decision.
"Either the options they prefer aren't available or they are unacceptable," explains Lyerly.
In the survey, the researchers presented four embryo disposition options: thawing and discarding; reproductive donation; indefinite freezing; and donation for research. The majority were unlikely to choose any of these options except for one: research donation.
In a previous paper published in Science, Lyerly reported that 60 percent would be likely to donate unused embryos for stem cell research, an option not readily available. But even if federal policies on funding stem cell research change, Lyerly says that doesn't solve patients' conundrum.
"For many of these patients, the need to make a decision about disposing these embryos is not discussed up front. Understandably, fertility patients have hard times thinking about destroying their embryos when they are emotionally and financially invested in trying to make a baby," she says.
The conundrum arises when reproductive goals change without a renewed discussion about what to do with the embryos that have been stored.
"Many centres don't make available all the options for disposition," Lyerly says.
"Even in places where embryo research is not conducted, it's possible that embryos can be transferred to another centre, yet this might not be discussed."
Two methods that were considered somewhat acceptable by about 20 percent of the fertility patients were placement of embryos in a woman's body at an infertile time, and the idea of a ritual disposal ceremony. Yet, Lyerly says these alternatives are rarely offered to patients even though "these may be the answers to many patients' desires as they allow the embryos to pass in a way that seems most respectful to them."
By bringing fertility patients' concerns to the forefront, Lyerly hopes the next step will be the development of clinical guidelines and ongoing informed consent processes for patients at various stages of fertility treatment. She also hopes it will encourage more detailed disclosure about the available disposition options and facilitate broad availability of disposition decisions that are morally acceptable to the majority of fertility patients.
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ZenMaster